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Role of Oxidative Stress in Hypersensitivity Reactions to Sulfonamides.
- Source :
-
Journal of clinical pharmacology [J Clin Pharmacol] 2020 Mar; Vol. 60 (3), pp. 409-421. Date of Electronic Publication: 2019 Nov 10. - Publication Year :
- 2020
-
Abstract
- Antimicrobial sulfonamides are important medications. However, their use is associated with major immune-mediated drug hypersensitivity reactions with a rate that ranges from 3% to 4% in the general population. The pathophysiology of sulfa-induced drug hypersensitivity reactions is not well understood, but accumulation of reactive metabolites (sulfamethoxazole [SMX] hydroxylamine [SMX-HA] and SMX N-nitrosamine [SMX-NO]) is thought to be a major factor. These reactive metabolites contribute to the formation of reactive oxygen species (ROS) known to cause cellular damage and induce cell death through apoptosis and necroptosis. ROS can also serve as "danger signals," priming immune cells to mount an immunological reaction. We recruited 26 sulfa-hypersensitive (HS) patients, 19 healthy control subjects, and 6 sulfa-tolerant patients to this study. Peripheral blood monocytes and platelets were isolated from blood samples and analyzed for in vitro cytotoxicity, ROS and carbonyl protein formation, lipid peroxidation, and GSH (glutathione) content after challenge with SMX-HA. When challenged with SMX-HA, cells isolated from sulfa-HS patients exhibited significantly (P ≤ .05) higher cell death, ROS and carbonyl protein formation, and lipid peroxidation. In addition, there was a high correlation between cell death in PBMCs and ROS levels. There was also depletion of GSH and lower GSH/GSSG ratios in peripheral blood mononuclear cells from sulfa-HS patients. The amount of ROS formed was negatively correlated with intracellular GSH content. The data demonstrate a major role for oxidative stress in in vitro cytotoxicity of SMX reactive metabolites and indicate increased vulnerability of cells from sulfa-HS patients to the in vitro challenge.<br /> (© 2019, The American College of Clinical Pharmacology.)
- Subjects :
- Adolescent
Adult
Aged
Anti-Infective Agents blood
Anti-Infective Agents metabolism
Blood Platelets metabolism
Cell Survival drug effects
Child
Drug Hypersensitivity blood
Drug Tolerance
Female
Glutathione metabolism
Healthy Volunteers
Humans
Leukocytes, Mononuclear metabolism
Lipid Peroxidation drug effects
Lymphocytes metabolism
Male
Middle Aged
Patients
Protein Carbonylation drug effects
Reactive Oxygen Species metabolism
Sulfamethoxazole adverse effects
Sulfamethoxazole analogs & derivatives
Sulfonamides blood
Sulfonamides metabolism
Young Adult
Anti-Infective Agents adverse effects
Drug Hypersensitivity etiology
Oxidative Stress drug effects
Sulfonamides adverse effects
Subjects
Details
- Language :
- English
- ISSN :
- 1552-4604
- Volume :
- 60
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- Journal of clinical pharmacology
- Publication Type :
- Academic Journal
- Accession number :
- 31709574
- Full Text :
- https://doi.org/10.1002/jcph.1535